10-year-old female with intragenic KANSL1 mutation, no KANSL1-related intellectual disability, and preserved verbal intelligence
Abstract
Koolen-de Vries Syndrome (KdVS), also referred to as 17q21.31 microdeletion syndrome, is caused by haploinsufficiency of the KANSL1 gene. This genetic disorder is associated with a clinical phenotype including facial dysmorphism, developmental delay, and friendly disposition, as well as mild-to-moderate intellectual disability. We present the case of a 10 year 8 month old female with KdVS due to a de novo intragenic KANSL1 mutation. At this time, she does not present with intellectual disability, and her verbal intelligence is relatively preserved, although she has perceptual deficits, developmental dyspraxia, and severe speech disorder. This case expands the mild end of the neurodevelopmental spectrum seen in children with de novo KANSL1 mutation and KdVS. © 2017 Wiley Periodicals, Inc.
INTRODUCTION
17q21.31 deletion syndrome, also referred to as Koolen-de Vries syndrome (KdVS; OMIM #610443), was first reported in 2006 and is estimated to occur 1 in 16,000 live births [Koolen et al., 2006]. The phenotype is caused by haploinsufficiency of the KAT8 regulatory NSL complex unit 1 (KANSL1) gene. Most affected individuals have a microdeletion of chromosome 17q21.31, but a small number of affected individuals have a de novo loss of function mutation in KANSL1 [Zollino et al., 2012; Koolen et al., 2012; Moreno-Igoa et al., 2015]. Features of the syndrome include hypotonia, developmental delay, verbal apraxia of speech, distinctive facial features, and variable degrees of intellectual disability [Egger et al., 2013; Mc Cormack et al., 2014; Koolen et al., 2016].Congenital heart malformations, urological issues, and seizures are not uncommon [Dornelles-Wawruk et al., 2013]. Recently, Zollino et al. [2015] compared features of patients with 17q21.31 deletions to patients with intragenic KANSL1 mutations and found that, in several individuals, including this patient (patient 24), the degree of intellectual disability was milder than previously described. However, detailed information about the neurodevelopmental phenotype was not provided. Koolen et al. [2016] summarized clinical features in an additional cohort of patients with KdVS and identified one patient with borderline intellectual disability (IQ = 73), but noted that in general most patients have a moderate level of delay.
This is the case report of a 10 year 8 month old female with KdVS caused by a de novo intragenic KANSL1 mutation. At this time, she does not present with KANSL1-related intellectual disability, and her verbal intelligence is intact. She has perceptual deficits, developmental dyspraxia, and severe speech disorder. This case expands the mild end of the neurodevelopmental spectrum seen in children with KdVS.
CLINICAL REPORT
The patient is the product of a full term 39.5 week pregnancy born to a 31 year-old gravida 2 para 2 Caucasian female and a 34 year-old Caucasian male. The pregnancy was complicated by bleeding at 10 weeks gestation, which later resolved. The pregnancy was unremarkable for infections, pre-term labor, hypertension, and gestational diabetes. The mother has Grave's disease and Hashimoto's thyroiditis and was taking Propylthiouracil (PTU) until the pregnancy was recognized at about 4 or 5 weeks gestation. Prenatal vitamins were taken inconsistently. There were no other exposures to drugs or alcohol.
A quadruple screen was positive for an increased risk of Trisomy 18. However, subsequent amniocentesis confirmed a normal 46,XX karyotype. Level II ultrasound at 17 weeks gestation showed echogenic bowel, which later resolved spontaneously. Follow up ultrasounds at 32 weeks and 39 weeks showed hydronephrosis bilaterally with mild caliectasis.
The patient was delivered vaginally with a birthweight of 3.6 kg (75–90th centile) and length of 50.8 cm (75–90th centile).
Family History
The patient is one of two children born to her parents. Her brother is in good health, although has ADHD-inattentive subtype.
The patient's mother has thyroid problems including Grave's disease and Hashimoto's thyroiditis, and a history of panic disorder. Her maternal aunt also has thyroid problems. Maternal grandmother underwent a thyroidectomy due to hyperthyroidism.
Her father is in good health, and has ADHD and a possible undiagnosed learning disorder. Paternal grandfather died at 46 due to brain cancer associated with Von Hippel-Lindau syndrome (VHL) and was also blind due to angiomas of the eyes; the patient's father tested negative for the familial VHL mutation. Paternal grandmother has breast cancer and is believed to have epilepsy.
Maternal ethnicity is Irish and English. Paternal ethnicity is Irish and German. Consanguinity is denied.
Developmental History
The newborn period was largely uncomplicated except for mild jaundice that resolved without phototherapy. Initial hearing screen was failed twice, which was then followed up with an Auditory Brainstem Response (ABR) that was normal. She did not have seizures, respiratory distress, or apnea in the newborn period. However, later in infancy she developed bronchitis and required nebulizer treatments for over 1 year. She was noted to be hypotonic, however, there were no problems feeding and weight gain was normal.
Shortly after birth she was noted to have left hip dislocation, and was later diagnosed with bilateral hip dysplasia. This was treated with a Pavlik harness, which she wore for her first 4 months of life. An X-Ray at 3 years of age showed the left acetabulum to be smaller than the right.
The patient also has vision abnormalities. At 3 months of age, she was diagnosed with accommodative esotropia and has been prescribed progressive bifocal corrective lenses. She has an intermittent alternating esotropia with a left hypertropia at distance, but the strabismus is small overall at distance. At near her esotropia is about 25 prism diopters with a dissociated vertical deviation observed where she has right hypertropia that is greater than the left hypertropia. She starts to see double any object greater than 4 inches from her nose. Her ocular motor skills are complicated by poor fixation and cogwheeling. She has been diagnosed with accommodative esotropia, residual alternating esotropia at near, deficiency of pursuits, deficiency of saccades, vertical hypertropia, and visual motor integration delay. Visual differences are believed to affect her depth perception.
Developmental milestones were globally delayed with walking at 18 months, her first words at 2 years 6 months, and independence in bowel and bladder function between 6 and 7 years.
Dysmorphic craniofacial features include midface hypoplasia, hypertelorism, sparse eyebrows, upward slanting palpebral fissures, tubular or pear-shaped nose with a bulbous nasal tip, long and prominent philtrum, everted lower lip, and abnormal hair/color texture. Her hair grows to a certain length and then stops growing completely. She has been noted to have an anterior open bite with edge-to-edge Class III malocclusion, open mouth posture at rest, open bite malocclusion, and forward tongue posture. Her teeth are small and widely spaced.
The patient has been followed in multiple specialty clinics since birth including ENT, cardiology, developmental pediatrics, genetics, craniofacial clinic, neurology, ophthalmology, neuropsychology, speech and language pathologists, and orthopedics. Routine cardiac evaluation, including echocardiogram prior to starting stimulant medications, was remarkable only for trivial tricuspid and mitral insufficiency. Each professional report makes note of her friendly, agreeable personality.
She had extensive genetic diagnostic workup that was unremarkable, therefore, clinical exome sequencing was pursued at 7 years of age, which identified a novel c.540delA p.(K180Nfs*22) frameshift mutation in exon 2 of KANSL1. The variant was Sanger confirmed, and Sanger confirmation in both parents confirmed this to be de novo. Although this variant has not been previously reported, other frameshift and nonsense mutations in exon 2 have been reported in other individuals with KdVS, supporting the diagnosis of KdVS in this patient [Zollino et al., 2015; Koolen et al., 2016]. There were no other pathogenic or likely pathogenic variants identified that would account for her phenotype.
CNS involvement
The patient was noted to have central hypotonia in infancy with joint laxity. Head ultrasound to evaluate for macrocephaly and positional plagiocephaly, which is suggestive of a congenital muscular torticollis although there was no diagnosis. Benign external hydrocephalus was present, with no shunt or drainage required. Macrocephaly at birth grew symmetrically over the years. MRI completed at approximately 3 years of age found mild prominence of the ventricles, and a mega cisterna magna. She was also noted to have a small pineal cyst without mass effect. Six months later, a follow up MRI revealed stable mild prominence of the ventricles, slight increased size of the pineal cyst but no solid mass and no parenchymal abnormality was identified. A follow up MRI at the age of 4 found the pineal cyst stable. She has no history of seizures; a 72 hr EEG performed at age 5 due to concern for staring spells was unremarkable.
Hearing impairment
She had multiple ear infections in infancy and has had five sets of bilateral pressure equalization (PE) tubes due to recurrent middle ear fluid. The first set was inserted at 17 months, significant drainage was noted, and she walked 1 month after. There is a history of some mild-to-moderate conductive hearing loss due to fluid accumulation. An audiological evaluation at 4 years of age was normal after the final set of PE tubes were inserted.
Speech and language
As an infant, her speech and language milestones were delayed and she was diagnosed with Childhood Apraxia of Speech (CAS), at 2 years of age. At 3 years of age she was further diagnosed with severe phonological disorder and moderate oral motor apraxia. At 10 years of age she no longer met the diagnostic criteria for CAS, but had 7 of 10 salient characteristics of CAS. This may indicate a positive response to therapeutic intervention. She developed an associated motor speech disorder with decreased intelligibility consistent with dysarthria as she grew older. She has a severe receptive and expressive language disorder, which was characterized by decreased vocabulary knowledge and use, auditory comprehension difficulties, and deficits in language expression. She presents with pragmatic language disorder, as well as mild oral apraxia.
Neurodevelopmental testing
At 10 years of age she was administered the Expressive One Word Picture Vocabulary Test, 4th Edition (EOWPVT-4) and the Receptive One Word Picture Vocabulary Test, 4th Edition (ROWPVT-4). She performed standard scores of 80 on both tests, which is low average (Table II).
Her performance on the WISC-IV (Table I) indicated a low-normal verbal intelligence with a composite score of 83, with a 95% confidence interval that her true score is between 77 and 91. She has a composite score of 59 in perceptual reasoning, 56 in working memory, and 53 in processing speed.
| Scaled score | Descriptive category | |
|---|---|---|
| Block design | 4 | Low average |
| Similarities | 7 | Average |
| Digit Span | 3 | Low |
| Picture concepts | 4 | Low |
| Coding | 2 | Low |
| Vocabulary | 1 | Low |
| Letter-number sequence | 2 | Low |
| Matrix reasoning | 2 | Low |
| Comprehension | 7 | Average |
| Symbol search | 1 | Low |
| Picture completion | 2 | Low |
| Cancellation | 4 | Low |
| Information | 5 | Low |
| Word reasoning | 7 | Average |
| Composite score | Descriptive category | |
|---|---|---|
| Verbal comprehension | 83 | Low average |
| Perceptual reasoning | 59 | Low |
| Working memory | 56 | Low |
| Processing speed | 53 | Deficient |
| Full scale IQ | 56 | Low |
She had normal scores (scaled scores between 7 and 13) on three subtests of the verbal domain: similarities (SS = 7), comprehension (SS = 7), and word reasoning (SS = 7). She did well with tasks that measured her abilities to evaluate and use past experiences, social judgement, abstract thinking, and was able to effectively integrate and synthesize different types of information to draw conclusions. In the vocabulary subtest of the verbal domain, she had a scaled score of 1, suggesting significant language formulation and word retrieval deficits.
Perceptually, she has significant deficits in processing speed. Tasks where she needed to use short term visual memory coupled with fine motor skills (coding) and visual prowess (symbol search) were significantly impaired. She was significantly impaired in perceptual reasoning subtests that were language and culture free (matrix reasoning), and that required her to distinguish between essential and nonessential details (picture completion).
The Woodcock Reading Mastery Tests, 3rd Edition (WRMT-III) had several standard scores well within normal (Table II). She had average-level capabilities in reading comprehension with a scaled score of 85, and scaled scores of 86 in word and passage comprehension. Listening comprehension was also within normal limits with a scaled score of 86. The contrast between perceptual and verbal domains is striking. Perceptual domain may be compromised by her significant and severe visual dysfunction.
| Standard score | Descriptive category | |
|---|---|---|
| Word identification | 64 | Low |
| Word attack | 80 | Low average |
| Basic skills | 71 | Low average |
| Word comprehension | 86 | Average |
| Passage comprehension | 86 | Average |
| Reading comprehension | 85 | Average |
| Listening comprehension | 86 | Average |
| Receptive and expressive one word picture vocabulary test | ||
| Expressive one word PVT | 80 | Low average |
| Receptive one word PVT | 80 | Low average |
Behavior
She has mild-to-moderate sensory dysfunction in multisensory processing, processing related to endurance/tone, modulation of sensory input affecting emotional response, and in behavioral outcomes of sensory processing.
The Child Behavior Checklist (CBCL) was completed by the patient's mother. Although her score on total competence was within the clinical range, her scores on activities and social scales were both within the normal range. All problem scales were within normal range for girls her age with the exception of attention deficit/hyperactivity problems scales which is consistent with her diagnosis of ADHD and her family history. She has few behavioral issues with the exception of problems consistent with ADHD-combined subtype.
DISCUSSION
This is a case of a 10 year 8 month old girl with intragenic KANSL1 mutation and confirmed diagnosis of KdVS. She has a learning profile characterized by normal verbal IQ, childhood apraxia of speech, oral motor apraxia, and significant perceptual processing deficits in addition to serious visual disturbances. She has multi-systemic involvement consistent with what has been reported in KdVS including enlarged ventricles, central hypotonia, hip dysplasia, minor morphogenic anomalies, and visual and hearing disturbances.
Her neurocognitive profile is compelling for several reasons. Despite having a severe speech-language disorder, her verbal intelligence is intact, which may indicate her speech deficit is a result in greater part motorically based. While verbal comprehension and reading skills are areas of relative strength, and have not been previously described to our knowledge, she has significant deficits to nonverbal domains that are not supported by brain imaging findings. To our knowledge, this is the first examination of perceptual processing deficits in this neurogenetic disorder. The query must be postulated: are the perceptual deficits a novel facet of neurodevelopment due to KANSL1 haploinsufficiency? It would be interesting to see if perceptual domains are significantly more impaired than verbal domains in those affected with KANSL1-related intellectual disability.
The complexity of her visual deficits and their relationship to the progression of perceptual deficits is not clear yet. Visual differences have previously been described within the 17q21.31 microdeletion population and were present in this case. Further research is warranted to investigate if phenotypic visual presentations exacerbate perceptual deficits among individuals with KdVS.
Although initial reports of KdVS did not include features of ADHD, Koolen et al. [2016] reported ADHD in 1/12 patients with mutation and 6/33 patients with 17q21.31 microdeletions. Detailed family history regarding whether these patients have any family history of ADHD was not available. This patient did have a positive family history of ADHD, and we wondered if this patient's ADHD-combined subtype is a combination of both the familial learning disabilities and KANSL1 haploinsufficiency, as well as to what degree this affects her academic performance [Samango-Sprouse et al., 2014, 2013]. It would be interesting to consider the potential association between genetic disruptions on chromosome 17 and an increased risk of ADHD, and consequent impact in academic domains.
Childhood apraxia of speech (CAS) has not been previously described in KdVS. This patient has had an excellent response to therapeutic intervention, which supported her verbal skill development rather nicely. Hyper-sociability, as well as a relatively strong memory for social cognition has also been described in KdVS [Egger et al., 2013]. These two aspects may lend themselves to increased verbal intelligence, which could be explored further by completing more detailed neurodevelopmental testing in other KdVS patients. Our findings expand the phenotypic presentations previously described in KdVS, particularly in regards to the neurodevelopmental phenotype, and suggest wider variability in the intellectual presentation of KdVS than what has previously been recognized.
